Why do clinical trials take so long?

Nia Abdullayeva

Introduction

Why is it that it takes about 12 years for a drug to go from lab to bedside, especially with the present-day funding for research and clear urgency for cures? What makes research take so long? And how can it be sped up? This article walks you through just that, in an effort to understand the challenges that drug development companies face, and what steps are taken to expedite this process.

Preclinical research is lengthy and multifaceted

Before a potential drug can even begin clinical trials, it needs to be thoroughly researched in the preclinical trial phase; this is a strenuous series of steps using animal models that need to be taken to submit the Investigational New Drug application (IND) to the Food and Drug Administration (FDA) in order to begin testing on human patients.

So what makes preclinical research take so long? First, researchers identify the "best" or the most chemically active version of the pharmacological compound (this is known as the drug candidate), followed by the tracking of absorption, distribution, metabolism, and excretion of the drug after it is ingested [1]. Then, everything from delivery of the drug to its dosage and timing needs to be determined, and this is done through further animal testing. The next steps include the formulation of ingredients in the delivered drug, extensive research on toxicology which takes a minimum of 12 weeks, and establishing a manufacturing process after the potential drug candidate successfully passes all the previous tests. The most critical step at this point is to design the next phase of research, clinical trials; this must be thoroughly revised since planning is where most mistakes can be avoided. The entirety of the preclinical research findings is finally compiled into the IND, the standard review of which takes 10 months according to the FDA [2].

Understandably, preclinical research takes on average 12 years and approximately 1.8 billion dollars to finance [1]. To do this, a myriad of trained investigators and clinicians need to be recruited. On top of that, animal research may not always reflect human processes; for example, while the SOD1 mouse research for ALS (Amyotrophic Lateral Sclerosis) gave insight into treatment of the rarer genetic version of the disease, it did not shed any light on treatment of the more common sporadic form which constitutes 95% of cases [3].

Not enough patients participate in clinical trials

Clinical trials are broken up into three phases of research on humans; the first phase involves healthy volunteers while the last two have actual patients participate. According to the New York Times, 1 in 5 cancer trials close because of insufficient enrollment [4]; by reducing the number of teams working towards a cure, the entire research movement is undermined, making all of the time and money spent thus far go to waste. The statistical disparity between the number of Americans who say they are willing to enroll in a clinical trial (72%) and the actual percentage that does (2%) is gravely astounding. In addition to that, only 6% of the critically sick enroll, causing only 6% of trials finish on time. Researchers experiencing an average 4.6-month delay are more fortunate still than those conducting 20% of clinical trials, who never enroll a single participant. Of those participants who do make it past these obstacles, only 70 to 75% of them actually complete a trial; the main reason of this is the lack of compliance with the prescription [5].

Right from the start, it can be said that recruitment for research on rarer diseases is difficult and often requires the collaboration of several countries. However, for the more general diseases, there exist other reasons for a lack of volunteers. Real patients face the gamble of being placed in the placebo control group, where their time and hopes will be invested in a "sugar pill". In addition to this, there is a lack of awareness of what a clinical trial is -- to the stunning degree that only a quarter of Americans can describe one. It is not made clear that participation is free and the placebo is not a "sugar pill" but a functioning standard of care. Sadly, little can be done but to motivate those who consider it too much effort to sign the detailed consent form. On the other hand, patients often do not want to give up alternative treatments for a research trial as is required in the conditions of the agreement, this makes them ineligible for the trial by default [5]. Moreover, the form itself creates trouble for illiterate participants from third world countries and has a lack of culturally specific explanations for consent for ethnic participants.

It takes a significant amount of work to conduct thorough clinical trials.

Presently, there is insufficient support from doctors. Whether it be from the fear of losing the patient or even lack of time and information to be up to date on new treatments and investigational drugs, doctors do not refer enough patients to clinical trials [5]. Thus, investigators are pushed to use smaller and smaller populations for research; however, statistical analysis of such results is unreliable. This gives rise to a disjointed effort to develop cures.

Should the nature of the delivery of the drug be complex, this extends the time required to set up and carry out research at the site. Non-standard delivery methods, such as those that require special equipment or trained staff, reduce the number of hospitals that are able to participate. Ideally, drugs in the form of a pill or drip are best. Also, delivery length should either be a single dose or a short course, not several years [6].

At the end of clinical trials, there is a follow-up period, this can take anywhere from a few months to 10 years and is important for clinicians to pick up on the long-term effects of the drug [6]. Should anything troubling arise, the drug needs to be immediately revised, recommencing clinical research.

How can we speed it up?

Since there are no contesters to the FDA in terms of the thoroughness of research required before release of a new drug, a standard 12-week long study cannot be made to take any less time. Nevertheless, there exist many solutions to smoothen out the transitions from one step of research to another. Some of these were already touched upon, such as international recruitment of patients, and more committed involvement of doctors. In like manner, clinicians are implementing the advice of experts on areas ranging from conducting the correct studies to using the correct drug candidates [1]. These seasoned individuals assist in providing solutions to inevitable problems and set milestones to keep developers on track.

Assistance also comes in the form of supplementary organizations such as Fastercures, which speeds up drug discovery during the preclinical phase, and the Muscular Dystrophy Association (MDA) Venture program which provides funding to stop sites from being shut down once they run out of money [1]. To organize the research process, there is the DLTA (drug lifecycle tracking application) that manages drug life cycle and regulatory review processes, sets milestones and priorities, and reports progress of all drug approval tasks {7].

For the research itself, new biotechnology in the form of biomarkers is able to indicate how a patient will respond to a particular drug, thus allowing to select patients most likely to do well with it [3][8]. With this tool, fewer patients will be needed for trials and they can be completed in shorter time spans. Additionally, IT is being implemented more and more to speed up data collection and analysis [9].

Development companies are encouraging more communication and accessibility. This has been achieved by the following methods: investing to create mobile stations in sites located in third world countries, storefront laboratories to draw blood, allowing clinicians to visit patients’ homes or having trials conducted over skype [10]. A big step forward was boosting recruitment through social media and connecting with local medical science officials to publicize and give tours of the sites, promoting awareness. Terri Robertson, senior director of clinical program development at AbbVie conducted a recent global experiment where she opened 40 clinical sites in 40 days. She attributed the success of her projects to the following points: a mass outreach effort for investigators, conducting assessments by phone, issuing non-negotiable contracts, qualifying each site in one visit, and having a 24/7 hotline [10]. Unsurprisingly, this allowed for 100% faster enrollment than existing trial sites and plants hope for faster, more efficient and ultimately more successful efforts in finding a cure.